Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons

Mardinly, Alan R.; Spiegel, Ivo; Patrizi, Annarita; Centofante, Eleonora; Bazinet, Jeremy Edmond Groshen; Tzeng, Christopher P.; Mandel‐Brehm, Caleigh; Harmin, David A.; Adesnik, Hillel; Fagiolini, Michela; Greenberg, Michael E.

doi:10.1038/nature17187

Cited by 160 publications

(199 citation statements)

References 39 publications

(48 reference statements)

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“…To test whether any modules reflect activity state, we assessed enrichment of a curated set of genes induced by neural activity (Table S4; Cho et al, 2016; Kim et al, 2010; Lacar et al, 2016; Mardinly et al, 2016). Three of the seven modules correlated with transcriptional subtype identity (black, purple, and midnight blue) were significantly enriched for genes induced by neuronal activity (Figures 3E and S5E; p < 0.01, hypergeometric test).…”

Section: Resultsmentioning

confidence: 99%

“…These weights were used to rank-order all expressed genes for input into a pre-ranked GSEA (Subramanian et al, 2005). Gene sets for the GSEA were derived from the Monocle2 differential gene tests described above or a curated list of neuronal activity genes (Cho et al, 2016; Kim et al, 2010; Lacar et al, 2016; Mardinly et al, 2016) using an adjusted p value cutoff of <0.01.…”

Section: Methodsmentioning

confidence: 99%

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Variation in Activity State, Axonal Projection, and Position Define the Transcriptional Identity of Individual Neocortical Projection Neurons

et al. 2018

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SUMMARY Single-cell RNA sequencing has generated catalogs of transcriptionally defined neuronal subtypes of the brain. However, the cellular processes that contribute to neuronal subtype specification and transcriptional heterogeneity remain unclear. By comparing the gene expression profiles of single layer 6 corticothalamic neurons in somatosensory cortex, we show that transcriptional subtypes primarily reflect axonal projection pattern, laminar position within the cortex, and neuronal activity state. Pseudotemporal ordering of 1,023 cellular responses to sensory manipulation demonstrates that changes in expression of activity-induced genes both reinforced cell-type identity and contributed to increased transcriptional heterogeneity within each cell type. This is due to cell-type biased choices of transcriptional states following manipulation of neuronal activity. These results reveal that axonal projection pattern, laminar position, and activity state define significant axes of variation that contribute both to the transcriptional identity of individual neurons and to the transcriptional heterogeneity within each neuronal subtype.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Variation in Activity State, Axonal Projection, and Position Define the Transcriptional Identity of Individual Neocortical Projection Neurons

et al. 2018

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“…Igf1 −/− mice have reduced numbers of PV + immunopositive neurons in the cortex and CA regions of the hippocampus, indicating that IGF1 has an important role in the development and maturation of PV + circuits in the brain (104). A recent study has revealed Igf1 as a key activity-regulated gene in vasoactive intestinal peptide (VIP) + inhibitory interneurons, which, in turn, influence net inhibition onto cortical pyramidal neurons (105). Furthermore, IGF1 promotes maturation of Cl − export and GABA hyperpolarization in CA1 neurons (30) and accelerates the developmental switch between NKCC1 and KCC2 chloride transporters in rat visual cortex (98).…”

Section: Discussionmentioning

confidence: 99%

Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

Banerjee

Rikhye

Breton-Provencher

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

159

202

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Rett syndrome (RTT) arises from loss-of-function mutations in methyl-CpG binding protein 2 gene (Mecp2), but fundamental aspects of its physiological mechanisms are unresolved. Here, by whole-cell recording of synaptic responses in MeCP2 mutant mice in vivo, we show that visually driven excitatory and inhibitory conductances are both reduced in cortical pyramidal neurons. The excitation-to-inhibition (E/I) ratio is increased in amplitude and prolonged in time course. These changes predict circuit-wide reductions in response reliability and selectivity of pyramidal neurons to visual stimuli, as confirmed by two-photon imaging. and increases KCC2 expression to normalize the KCC2/NKCC1 ratio. Thus, loss of MeCP2 in the brain alters both excitation and inhibition in brain circuits via multiple mechanisms. Loss of MeCP2 from a specific interneuron subtype contributes crucially to the cell-specific and circuit-wide deficits of RTT. The joint restoration of inhibition and excitation in cortical circuits is pivotal for functionally correcting the disorder.MeCP2 | E/I balance | parvalbumin neurons | IGF1 | chloride transporters S ynaptic excitation (E) and inhibition (I), along with the neuronal balance of excitation and inhibition (E/I), is key to the function of brain circuits, and is often disrupted in neurodevelopmental disorders, including autism spectrum disorders (ASDs) (1-3). Rett syndrome (RTT) is a severe neurodevelopmental and adult disorder that arises from sporadic loss-of-function mutations in the X-linked (Xq28) methyl-CpG binding protein 2 gene (Mecp2) encoding the protein MeCP2 (4-7). MeCP2 is a critical regulator of brain development and adult neural function (8), and arrested brain maturation due to synaptic dysfunction is one of the hallmarks of RTT (3). However, the effects of MeCP2 on excitatory and inhibitory synaptic mechanisms in vivo, and on neuronal and circuit function underlying RTT pathophysiology, are unknown.MeCP2 is ubiquitously expressed in multiple cell types and subregions of the brain (4, 6, 9), including inhibitory interneurons, and has cell-autonomous as well as non-cell-autonomous effects (10); thus, it has been particularly challenging to identify its role in cell-specific brain circuits. Anatomically diverse inhibitory interneuron subtypes with distinct physiological signatures influence different aspects of neocortical function and behavior (11,12). Soma-targeting parvalbumin-expressing (PV + ) and dendritetargeting somatostatin-expressing (SOM + ) interneurons are the two major nonoverlapping populations of interneurons in mice that target cortical pyramidal neurons (13). Inhibition by PV + and SOM + neurons powerfully influences neuronal responses and circuit computations in visual cortex (14-17). Deletion of MeCP2 from all forebrain GABAergic interneurons recapitulates key aspects of RTT (18), demonstrating that altered inhibitory function is an important facet of RTT pathophysiology. Indeed, a major phenotype of MeCP2 reduction in individuals with RTT and in mouse models is ...

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“…Such intrinsic processes are thought to cooperate with the interneuron's environment to establish neuronal circuits and brain connectivity in the adult 6 . For example, after arrival in the cortex, neuronal activity affects several aspects of interneuronal development [7][8][9] . The authors studied the migration pathways of two types of interneuron -one characterized in the adult by expression of the protein somato statin, the other by expression of the protein parvalbumin.…”

Section: H R I St I a N M Ay E R And G O R D F I S H E L Lmentioning

confidence: 99%

“…But several TCA intermediates are present in the circulation at substantial levels, and some of them, such as citrate, flow into and out of the bloodstream to a greater extent than does succinate 9 . The finding that circulating succinate has a well defined, and perhaps even medically impor tant, metabolic role raises the possibility that circulating TCA intermediates will more gen erally prove to be vital metabolic players.…”

mentioning

confidence: 99%

Developing neurons are innately inclined to learn on the job

Mayer

Fishell

2018

Nature

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Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons

Cited by 160 publications

References 39 publications

Variation in Activity State, Axonal Projection, and Position Define the Transcriptional Identity of Individual Neocortical Projection Neurons

Variation in Activity State, Axonal Projection, and Position Define the Transcriptional Identity of Individual Neocortical Projection Neurons

Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

Developing neurons are innately inclined to learn on the job

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